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PubMed1997

Risk of malignancy and death in neurofibromatosis.

OBJECTIVE AND METHODS: Neurofibromatoses are cancer-prone hamartomatoses that involve a variety of tissue and cell types. As part of a population-based clinical and genetic study of neurofibromatosis in northern Finland, all surgical and autopsy specimens of neurofibromatosis patients were retrieved and histologic slides were reviewed. RESULTS: Specimens were available for 69 of the 197 neurofibromatosis type 1 patients identified. Six malignant peripheral nerve sheath tumors and nine other malignant tumors were detected. In this study, the risk for neurofibromatosis-related malignancy was 8%. Nine neurofibromatosis type 1 patients died, at a mean age of 37 years. The cause of death was related to neurofibromatosis in eight. CONCLUSIONS: The risk of developing malignant tumors and early death is increased in patients with neurofibromatosis, the most common malignancy being malignant peripheral nerve sheath tumors. These risks need to be recognized, and the families should be advised to seek genetic counseling and proper follow-up.

Adolescent↗

PubMed1996

[Endocrinologic complications of neurofibromatosis type 1].

Neurofibromatosis type 1 is the most common autosomal dominant inheritable disease, which is often associated with secondary forms of hypertension and with tumors of neuroectodermal origin. The authors present the results of evaluation of 60 members of 3 families. Of the 60 family members, 13 subjects had symptoms of neurofibromatosis type 1 disease, of which 7 subjects were evaluated. The case histories of patients are discussed: (1) An incidentally discovered adrenal tumor was proved to be a pheochromocytoma. (2) Because of complaints similar to thyrotoxicosis, thyrostatic drugs were administered for years without effect and, finally, an adrenal phaeochromocytoma was diagnosed after the presence of neurofibromatosis was established. (3) Preeclamptic pregnancy of a young primigravida complicated with severe HELLP syndrome (hemolysis-elevated liver enzymes-low platelet count) led to thorough evaluation which revealed renal artery stenosis. In this patient, percutaneous renal artery angioplasty resulted in a complete cessation of hypertension. (4) Glucocortocoid replacement therapy in a patient with neurofibromatosis type 1 resulted in a complete normalization of both secondary adrenal insufficiency and a previously unexplained iron-refractor iron-deficient anemia. The case histories of the patients demonstrate a lack of in-depth knowledge of neurofibromatosis in clinical practice. A regular follow-up of neurofibromatosis patients is suggested in specialized health centers.

Adrenal Gland Neoplasms↗

PubMed1998

Seizures in neurofibromatosis 1.

Neurofibromatosis 1 is a common, genetically transmitted neurodevelopmental disorder with a high potential to cause subcortical focal brain lesions. Although seizures occasionally complicate neurofibromatosis 1, they have not been characterized adequately in the disease. Other phacomatoses with attendant subcortical focal brain lesions have been associated with an evolution from generalized to focal-onset epilepsy. This evolution may be related to the cortical dysplasias that also appear in such disorders. Cortical dysplasias, although occasionally found in neurofibromatosis 1 epileptic patients, are not as frequent as in other phacomatoses. The authors retrospectively screened 499 neurofibromatosis 1 patients for the prevalence and etiology of seizures, their response to therapy, and the evolution of seizure type over time. The prevalence of epileptic seizures (4.2%) was about twice the prevalence in the general population. There were no significant cortical dysplasias identified radiographically nor was there a relationship among the presence of subcortical focal brain lesions and seizure type, response to treatment, or evolution of epilepsy in the neurofibromatosis 1 population. The authors' data do not suggest an ontogeny of epilepsy in neurofibromatosis 1 that is different from the general epileptic population.

Adolescent↗

PubMed1995

Reduced expression of neurofibromin in the soft tissue tumours obtained from patients with neurofibromatosis type I.

1. We analysed the expression of neurofibromin mRNAs, encoded by the gene responsible for neurofibromatosis type 1, and of neurofibromin protein in nine soft tissue tumours by S1 nuclease mapping and Western blot analyses. Four tumours were obtained from patients with neurofibromatosis type 1, comprising two neurofibromas, one fibrolipoma and one malignant schwannoma, and five neurogenic tumours were obtained from non-neurofibromatosis type 1 patients. 2. All tumours, except for a malignant schwannoma, similarly expressed three species of mRNA encoding neurofibromin, an isoform with the insertion of 21 amino acids in the domain related to ras GTPase-activating protein, and an N-terminal isoform lacking this domain. 3. Western blot analysis demonstrated deficiency of neurofibromin in the tumours derived from three out of the four neurofibromatosis type 1 patients: a fibrolipoma, a malignant schwannoma and a neurofibroma. In contrast, reduction in neurofibromin was not detected in the five tumours obtained from non-neurofibromatosis type 1 patients. Furthermore, the expression of ras GTPase-activating protein was detected in all nine tumours examined. 4. The undetectable or reduced level of neurofibromin in the tumours obtained from neurofibromatosis type 1 patients suggests that this deficiency is closely related to their tumourigenesis.

Adult↗

PubMed2006

Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.

BACKGROUND & AIMS: Intestinal neurofibromatosis (Online Mendelian inheritance in Man database number 162220) is an alternate form of neurofibromatosis. Patients present with neurofibromas limited to the intestine in the absence of any other typical features of NF1 and NF2. At present, the molecular basis of intestinal neurofibromatosis remains elusive. The aim of the present study was to find the gene responsible for intestinal neurofibromatosis and to characterize functionally the mutation. METHODS: Three candidate genes (NF1, KIT, and PDGFRA) were screened for mutations in 3 sisters diagnosed with intestinal neurofibromatosis. Five tumors were available for pathologic examination. Activation (phosphorylation) of PDGFRalpha was subsequently tested by Western blot analysis on a transfected 293T and Ba/F3 cell line. RESULTS: We found an inherited mutation (Y555C) in the juxtamembrane domain of PDGFRA in the affected individuals. The Y555C mutation leads to autophosphorylation and thus activation of PDGFRalpha. These observations confirm that PDGFRalpha(Y555C) is an oncogenic kinase. The clinical phenotype in the reported family resembles the syndrome of familial gastrointestinal stromal tumors (familial GIST). Somatic activating mutations in KIT and PDGFRA are frequent in sporadic GISTs, and mutations in both genes have also been described in familial GISTs. The tumors in the reported family are morphologically identical to intestinal neurofibromas, but, immunohistochemically, they do not express S100 or any of the known GIST markers. CONCLUSIONS: The inherited PDGFRA mutation in the reported family shows that intestinal neurofibromatosis is allelic to familial GIST caused by PDGRA mutations. We therefore propose that these tumors be classified as familial KIT-negative gastrointestinal stromal tumors.

Adult↗

PubMed1997

Meningioangiomatosis is associated with neurofibromatosis 2 but not with somatic alterations of the NF2 gene.

Meningioangiomatosis occurs sporadically and in patients with neurofibromatosis. The literature, however, is unclear concerning the type of neurofibromatosis associated with meningioangiomatosis. Because determining which form of neurofibromatosis predisposes to meningioangiomatosis would clarify the genetic alterations of this lesion, we reviewed all reported cases of meningioangiomatosis associated with neurofibromatosis in light of current diagnostic criteria for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2). All well-documented cases of meningioangiomatosis occurred in the setting of NF2, implying that germline alterations of the NF2 gene predispose to meningioangiomatosis. To determine whether sporadic (non-NF) cases of meningioangiomatosis arise from somatic alterations of the same gene, we screened the NF2 gene for mutations in 12 sporadic cases of meningioangiomatosis and in constitutional DNA from 6 of these 12 patients. No mutations were found in either the lesional or constitutional DNA, which suggests that sporadic meningioangiomatosis is not a forme fruste of NF2 and that somatic alterations of the NF2 gene do not play a major role in sporadic meningioangiomatosis. For some tumor suppressor genes, germline mutations may predispose to specific tumors, while similar sporadic lesions only rarely suffer somatic mutations in these genes. The present findings suggest a similar dichotomy for the NF2 gene in meningioangiomatosis.

Angiomatosis↗

PubMed2003

Cochlear implantation in a patient with neurofibromatosis type 1 and profound hearing loss: evidence to support a cochlear site of lesion.

OBJECTIVE: To determine the efficacy of cochlear implantation in an individual with neurofibromatosis type 1 and profound hearing loss and to determine, to the extent possible in a living subject, the site of lesion of the hearing loss in an individual with neurofibromatosis type 1. STUDY DESIGN: Postoperative assessment of an adult male with neurofibromatosis type 1. SETTING: The study was completed in the Departments of Otolaryngology and Audiology, University of Massachusetts Medical Center, Massachusetts. PATIENTS: One adult male with neurofibromatosis type 1 and bilateral, chiefly profound, sensorineural hearing loss. INTERVENTIONS: The subject underwent cochlear implantation as treatment of bilateral, chiefly profound sensorineural hearing loss. MAIN OUTCOME MEASURES: Outcome measures include results of electrical auditory brainstem response testing, electrical compound action potential measures, and speech recognition scores. RESULTS: Results of testing revealed expected latencies of waves II, III, and V of the electrical auditory brainstem response, measurable compound action potentials across virtually the entire length of the electrode array, and high levels of open-set, auditory-only speech understanding. CONCLUSIONS: This is the first case report describing the outcome of cochlear implantation in a patient with neurofibromatosis type 1. Composite test results support the absence of VIIIth nerve degeneration or other anomalies, indicating a cochlear site of lesion for the hearing loss in this patient. Based on the results of this investigation, standard cochlear implantation should be considered a viable option and the first line of therapy for the treatment of bilateral, severe to profound sensorineural hearing loss in patients with neurofibromatosis type 1 and normal, VIIIth nerve radiographic findings.

Adult↗

PubMed2004

Hearing changes after diagnosis in neurofibromatosis type 2.

OBJECTIVE: Describe the changes in hearing ability and progression of disease over time in subjects with neurofibromatosis Type 2 enrolled in a multicenter natural history study of vestibular schwannomas in neurofibromatosis Type 2. STUDY DESIGN: Retrospective clinical study. SETTING: International neurofibromatosis Type 2 tertiary care centers. PATIENTS: Study participants had a clinical diagnosis of neurofibromatosis Type 2, at least one untreated vestibular schwannoma, and were at least 5 years old. Sixty-three subjects (108 ears) with audiology data at either short-term follow-up (7 mo-2 yr) or long-term follow-up (3-5 yr) after diagnosis were examined in this study. MAIN OUTCOME MEASURES: Changes in four-frequency pure-tone average and speech discrimination score before any treatment intervention for both follow-up intervals. RESULTS: Within 2 years of the diagnosis of neurofibromatosis Type 2, 27% of the ears experienced a significant loss in pure-tone average relative to diagnosis, and 73% of the ears experienced no significant change in hearing. CONCLUSION: Newly diagnosed neurofibromatosis Type 2 patients who do not require immediate treatment of both vestibular schwannomas are likely to have stable hearing in the unoperated ear(s) for approximately 1 to 2 years.

Adolescent↗

PubMed1995

Screening of neurofibromatosis type 1 gene: identification of a large deletion and of an intronic variant.

Neurofibromatosis type 1 of von Recklinghausen is a common autosomal dominant disorder, characterized by peripheral neurofibromas, café-au-lait spots and Lisch nodules of the iris. The high mutation rate at the neurofibromatosis type 1 locus results in a wide range of molecular abnormalities. We have screened seven different exons of the neurofibromatosis type 1 gene, including those codifying for the GAP-related domain, using the RNA-Single Strand Conformation Polymorphism (RNA-SSCP) method in a series of 59 neurofibromatosis type 1 patients. We have also analyzed four intragenic repeats and one RFLP to detect hemizygosity and evaluate informativeness in at-risk families. One deletion and a new intronic normal variant have been detected. Thus the majority of Neurofibromatosis type 1 chromosomes have not been characterized, confirming difficulty in providing proper genetic counselling in neurofibromatosis type 1 families, even following extensive DNA analysis.

Alleles↗

PubMed2000

Relationship of cognitive functioning, whole brain volumes, and T2-weighted hyperintensities in neurofibromatosis-1.

Using quantitative magnetic resonance imaging morphometry, we report that the whole brain volumes of patients with neurofibromatosis-1 are significantly larger than normal, confirm the prevalence of macrocephaly as about 50%, and report that macrocephaly in patients with neurofibromatosis-1 does not appear to be related to the familial or sporadic origin of the neurofibromatosis-1 or to the presence or absence of T2-weighted hyperintensities. No strong relationship emerged between the extent of neurofibromatosis-1-associated impairment of cognitive functions and degree of macrocephaly; however, the macrocephalic neurofibromatosis-1 group did have a significant verbal impairment relative to the nonmacrocephalic neurofibromatosis-1 group in vocabulary (P < .009).

Adolescent↗

PubMed2003

Neurofibromatosis 2 in the pediatric population.

Neurofibromatosis 2 is a severe autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas and other benign tumors of the nervous system. Excellent natural history studies exist for adults with neurofibromatosis 2, but limited outcome data are available for children with neurofibromatosis 2. In this study, we present clinical data on 12 patients with neurofibromatosis 2 and age at diagnosis before 18 years. Full record review included surgical reports, pathology reports, and imaging studies; all patients were personally examined by a single author. One third of the patients presented with hearing impairment and another third presented with other cranial nerve dysfunction. Tumor load was extensive, including cranial meningiomas in 75%, cranial schwannomas other than vestibular schwannomas in 83%, and spinal cord tumors in 75%. Family history was present in two thirds of the patients. Surgical removal of vestibular schwannomas was performed in 58%; none had full preservation of hearing postsurgery. Functionally, 75% of children had hearing loss, 83% had visual impairment, 25% had abnormal ambulation, and 25% were performing below grade level. In conclusion, increased clinical awareness, better imaging techniques, and molecular diagnostics have made pediatric diagnosis of neurofibromatosis 2 feasible, but outcomes appear to be worse than in adult patients. Further work is needed to determine optimal management of pediatric neurofibromatosis 2.

Adolescent↗

PubMed2003

Functional magnetic resonance imaging of phonologic processing in neurofibromatosis 1.

Neurofibromatosis 1 is associated with reading disabilities, but few associations between neuroanatomic abnormalities and reading problems have been found. We examined the neuronal bases for phonologic processing, a core component of learning to read, in 15 individuals with neurofibromatosis 1 and 15 controls using functional magnetic resonance imaging (MRI). Our results revealed differential use of inferior and dorsolateral prefrontal cortical areas relative to posterior (temporal, parietal, and occipital) cortices for participants with neurofibromatosis 1 compared with controls during phonologic (rhyme) decisions. In addition, similar to previous brain imaging studies of reading deficits in the general population, poorer performance on one of the phonologic decision tasks was associated with increased signal change in the right superior temporal gyrus for the neurofibromatosis 1 group. Behavioral performance on the functional MRI tasks was related to academic reading measures for the neurofibromatosis 1 group. The differential patterns of functional connectivity observed here lend support to previous morphologic studies that suggested inferior frontal and superior temporal areas to be important mediators of reading and language development in neurofibromatosis 1.

Adolescent↗

PubMed1993

Neurofibromatosis type 1: magnetic resonance imaging findings.

The purpose of this study was to determine the locations and characterize the types of brain abnormalities noted on brain magnetic resonance imaging in patients with probable and definite neurofibromatosis type 1. Patients with definite neurofibromatosis type 1 (n = 17) were studied when clinically indicated, and patients with probable neurofibromatosis type 1 (n = 9) were studied to evaluate for asymptomatic optic pathway glioma. Of the 26 patients evaluated, 14 (53%) had high-intensity signal abnormalities and 11 (42%) had significant structural abnormalities. Subsequent clinical follow-up has confirmed conversion to a definite neurofibromatosis type 1 diagnosis in three of the four cases of probable neurofibromatosis type 1 who had high-intensity signal abnormalities. The most common locations of high-intensity signal lesions were in the globus pallidus of the basal ganglia and cerebellar white matter. Tortuous or thickened optic nerves and/or optic chiasm were seen in eight cases. Brain magnetic resonance imaging scans frequently reveal high-intensity signal lesions and structural abnormalities in selected patients with both probable and definite neurofibromatosis type 1. These findings may allow for a definitive diagnosis in clinically probable cases.

Adolescent↗

PubMed1990

[Encephalic lesions in neurofibromatosis: clinical manifestations and typical magnetic resonance findings].

Neurofibromatosis is the commonest neuroectodermal disease. It is characterized by dysplasias and/or tumors of organs and tissues derived from the embryonic ectoderm, mesoderm and endoderm, and most frequently presents with nervous system and cutaneous lesions. It can be classified as neurofibromatosis type 1 (NF-1 or von Recklinghausen disease) and neurofibromatosis type 2 (NF-2 or bilateral acoustic neurofibromatosis). In order to assess clinical presentation of the disease and diagnostic value of Magnetic Resonance Imaging (MRI), the authors retrospectively evaluated the clinical records and the cranial MR studies of 21 patients with neurofibromatosis (18 with NF-1 and 3 with NF-2). Distinctive abnormalities between the two types were found in both clinical presentation and MR studies. Clinically, NF-1 patients presented most often with blindness, while NF-2 patients were deaf and had fewer cutaneous lesions. The evaluation of MR studies showed that NF-1 patients were more likely to be affected with intracranial gliomas, predominantly of the optic pathways. Moreover, foci of prolonged T2 relaxation were frequently observed, primarily in the globus pallidus of the basal ganglia and in the dentate nucleus of the cerebellum. Some of the foci in the globi pallidi exhibited increased signal intensity on T1-weighted images as well. NF-2 patients more frequently presented with bilateral acoustic schwannomas, meningiomas and cerebral white matter foci of prolonged T2 relaxation, but they did not have dentate and basal ganglia lesions. The authors conclude that as a rule the manifestations of NF-1 and NF-2 on cranial MRI are separate and distinct; they do not overlap. MRI is an useful clinical tool for the diagnosis and the follow-up of patients with neurofibromatosis.

Adolescent↗

PubMed1985

[Neurofibromatosis associated with intra- and extracranial aneurysms and extracranial vertebral arteriovenous fistula].

Neurofibromatosis associated with vascular disorders is generally known as a vascular neurofibromatosis. In the neurosurgical aspect, it has been pointed out that "moyamoya disease" -like stenosis and/or occlusion of the internal carotid artery are seen in some of the patients with neurofibromatosis. This 58-year-old female with multiple café-au-lait spots and neurofibromas all over the body was admitted to our hospital with complaints of left orbital tumor and tinnitus. She had been suffering from the left intraorbital neurofibroma since ten years of age. Radiological examinations revealed left intraorbital neurofibroma extending into the intracranial cavity, multiple aneurysms and arteriovenous fistula. The aneurysms were located at the left vertebral-posterior interior cerebellar artery junction and at the extracranial internal carotid artery. The arterio-venous fistula was demonstrated at the left extracranial vertebral artery. Pathological changes of the blood vessels in the vascular neurofibromatosis are essentially obstructive lesions due to intimal thickening. Only few cases of neurofibromatosis associated with aneurysms and arteriovenous fistula have been reported, and eleven cases of them could be reviewed in the literature. Six are with intracranial aneurysms, two with extracranial aneurysms and three with extracranial vertebral arteriovenous fistula,. It is interesting that in all cases the extracranial vertebral arteriovenous fistula are located on the left side. This is corresponding to the fact that the bone defect around the asterion is predominantly seen on the left side in cases of neurofibromatosis.

Arteriovenous Malformations↗

PubMed1984

Neurofibromatosis and spontaneous hemothorax in pregnancy: two case reports.

Two cases of spontaneous hemothorax in pregnant women with neurofibromatosis are reported. Effects of pregnancy on the clinical course of neurofibromatosis are known to include worsening of cutaneous lesions, increased incidence of hypertension, and renal artery rupture. However, vessel wall rupture into the pleural cavity in areas of vascular neurofibromatosis is previously unreported. Contributing factors may include normal hemodynamic changes of the puerperium and pathological alterations of preexisting areas of neurofibromatosis. Because the incidence of vascular neurofibromatosis is not known and is difficult to diagnose, the serious morbidity and mortality encountered in this group place all pregnant patients with neurofibromatosis in a high-risk obstetric category.

Adult↗

PubMed1995

Proton MR spectroscopy in patients with neurofibromatosis type 1: evaluation of hamartomas and clinical correlation.

PURPOSE: To use proton MR spectroscopy in patients with neurofibromatosis type 1 to determine: (a) the spectroscopic characteristics of hamartomas and compare them with that of gliomas; (b) whether differences exist between patients with and without learning disabilities; and (c) spectroscopic patterns in normal-appearing brain (by MR imaging) in patients with and without focal lesions. METHODS: Seventeen proton MR spectroscopy volumes were obtained in 10 patients with neurofibromatosis type 1 (including hamartomas, N = 7; normal-appearing brain, N = 10). Seven patients had learning disorders, and 3 were mentally normal. Ten healthy volunteers and 10 patients with pathologically proved gliomas (all grades) were also examined. N-Acetyl aspartate/creatine, creatine/choline, and N-acetyl aspartate/choline ratios were calculated for all samples. RESULTS: (a) Hamartomas showed higher N-acetyl aspartate/creatine, creatine/choline, and N-acetyl aspartate/choline ratios than gliomas. Hamartomas showed N-acetyl aspartate/creatine, creatine/choline, and N-acetyl aspartate/choline ratios similar to those of healthy volunteers. (b) No significant differences in N-acetyl aspartate/creatine, creatine/choline, and N-acetyl aspartate/choline ratios were found in patients who had neurofibromatosis type 1 with and without learning disabilities. (c) N-acetyl aspartate/creatine, creatine/choline, and N-acetyl aspartate/choline ratios were similar for patients who had neurofibromatosis type 1 with and without focal hamartomas and in healthy volunteers. CONCLUSIONS: (a) Hamartomas have a proton MR spectroscopy pattern different from that of glioma and similar to that of normal brain. (b) As performed in this study, proton MR spectroscopy did not show significant differences in patients who had neurofibromatosis type 1 with and without learning disabilities. (c) Patients who have neurofibromatosis type 1 with and without hamartomas seem to have normal intervening brain by proton MR spectroscopy when compared with healthy volunteers.

Adolescent↗

PubMed1997

Segmental neurofibromatosis: case reports and review.

Segmental neurofibromatosis (neurofibromatosis type V) is a rare disorder characterized by café-lu-lait macules and neurofibromas, or only neurofibromas, limited to one region of the body. Three patients with segmental neurofibromatosis are described, and cases of this condition in the world literature are reviewed. Segmental neurofibromatosis has only been described in 82 patients, including our three. The median age at onset was 28 years and the incidence was higher in women (58%). The neurofibromas most commonly occupied either a cervical or thoracic dermatome and were unilateral, occurring more often on the right side (43 patients) than the left (34 patients). Café-au-lait macules were present in 26% of patients. Axillary freckling was described in only nine patients. Disease-associated systemic involvement was uncommon. Most patients with segmental neurofibromatosis (93%) do not have a family history of neurofibromatosis.

Adult↗